Proof Of Concept: Enthesitis and New Bone Formation In Spondyloarthritis Are Driven By Mechanical Strain and Stromal Cells

Peggy Jacques¹, Stijn Lambrecht¹, Eveline Verheugen¹, Elin Pauwels², Marleen Verhoye³, Annemie Van der Linden³, George Kollias⁴, Rik J. Lories⁵ and Dirk Elewaut⁶, ¹Dept of Rheumatology, Laboratory for Molecular Immunology and Inflammation, Ghent University, Ghent, Belgium, ²Dept of Physics and Astronomy, UGCT, Ghent University, Ghent, Belgium, ³Bio-imaging Lab, University of Antwerp, Antwerp, Belgium, ⁴Institute of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece, ⁵Dept of Development and Regeneration, Laboratory for Skeletal Development and Joint Disorders, KU Leuven, Leuven, Belgium, ⁶Rheumatology, Department of Rheumatology Ghent University Hospital, Ghent, Belgium

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Enthesitis and spondylarthritis

Session Information

Title: Spondylarthropathies and Psoriatic Arthritis - Pathogenesis, Etiology

Session Type: Abstract Submissions (ACR)

Background/Purpose: Spondyloarthritides (SpA) are characterised by both peripheral and axial arthritis. Hallmarks of peripheral SpA are the development of enthesitis, most typically of the Achilles tendon and plantar fascia, and new bone formation. This study was undertaken to unravel the mechanisms leading towards enthesitis and new bone formation in preclinical models of SpA. TNF^Δ^ARE mice are an established model for SpA, characterized by an enhanced TNF messenger RNA stability, which leads to the development of peripheral and axial arthritis (sacroiliitis, spondylitis), and Crohn´s like ileitis.

Methods: To study the development of enthesitis in relation to mechanical strain, hind limb unloading of TNF^ΔARE mice was performed, followed by histological analysis. Activation of extracellular signal-regulated kinase (Erk1/2) and p38 pathways in response to mechanical strain was studied on Achilles tendon lysates. In addition, TNF^ΔARE mice were treated with small molecular inhibitors of Erk1/2 and p38. Since new bone formation does not occur in TNF^ΔARE mice, the collagen antibody-induced arthritis model, which is also characterized by enthesitis, was used to study this particular feature. Hind limb unloading was again performed, followed by histological analysis and micro-CT.

Results: We demonstrated that the first signs of inflammation in TNF^Δ^ARE mice were found at the entheses. Importantly, enthesitis occurred equally in the presence or absence of mature T and B cells, underscoring the importance of stromal cells. Hind limb unloading in TNF^Δ^ARE mice significantly suppressed inflammation at the synovio-entheseal complex of the Achilles tendon compared to weight bearing controls. Erk1/2 signalling played a crucial role in mechanotransduction associated inflammation. Furthermore, new bone formation was strongly promoted at entheseal sites by biomechanical stress and correlated with the degree of inflammation.

Conclusion: These findings provide a formal proof of the concept that mechanical strain drives both entheseal inflammation and new bone formation in SpA.

Disclosure:

P. Jacques,
None;

S. Lambrecht,
None;

E. Verheugen,
None;

E. Pauwels,
None;

M. Verhoye,
None;

A. Van der Linden,
None;

G. Kollias,
None;

R. J. Lories,

Pfizer Inc,

Celgene,

Abbvie,

Merck Pharmaceuticals,

Janssen Pharmaceutica Product, L.P.,

D. Elewaut,
None.

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